Hepatocellular carcinoma (HCC) is one of the most fatal malignancies in the world. Five-year survival rate of the disease is only 10%. The incidence of HCC has been steadily rising in the US. SEER data show that the rate more than doubled during the past 30 years. Although HCC is still rare in the US, the rapid increase in incidence has raised concerns on possible changes in underlying risk of the disease. Emerging evidence suggests that the biologic consequences of energy imbalance resulting from a lifestyle of high-calorie diets and physical inactivity may play a role in the etiology of HCC. This possible link of lifestyle to HCC has significant implications in public health because the increasing prevalence of overweight and obesity in our societies indicates that the incidence of HCC may continue to rise accordingly. Evidence also indicates significant host susceptibility to HCC reflected by low penetrance single nucleotide polymorphisms involved in regulation of cell proliferation, apoptosis, immune response to viral infection, inflammation, and other cancer-related cellular activities. To confirm if energy imbalance is independently involved in the etiology of HCC and to identify what genetic susceptible factors are associated with HCC risk, we propose an epidemiologic study of HCC in the states of Connecticut and New Jersey. The study will examine all known and suspected risk factors of HCC among Americans and evaluate the possible link of HCC to lifestyle factors related to energy balance. The investigation will also assess genetic polymorphisms in a genome- wide scope to determine host susceptibility to HCC. Synergistic interplay between energy imbalance and hepatitis virus infection will be another focus of this investigation. A population- based case-control study is designed to investigate these issues. The study will enroll 1,250 incident HCC cases through rapid case ascertainment. Two thousand and five hundred population controls with frequency match to cases on age, gender, race and state will also be recruited. The control subjects will be selected randomly from the state residents through random digital dialing. Questionnaire information and biologic specimens will be collected to assess the exposure of known and suspected risk factors of HCC and to examine possible genetic susceptibility and host- environment interaction. The study will generate valuable information on HCC in the US and may identify risk factors responsible for rising HCC in the US.